tbuckley/cabot-search huggingface dataset:
PB2315: PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A RETROSPECTIVE STUDY OF THE ZR OR ZRM REGIMEN (ZANUBRUTINIB, RITUXIMAB, METHOTREXATE)
Authors: Yue Teng, Weiyan Tang, Zhiya Wu, Yuxin Du, Jianqiu Wu
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphoma. Most PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). High dose systemic methotrexate (HD-MTX) plays an important role in the treatment of PCNSL, but patients cannot tolerate or are not suitable for HD-MTX are often encountered clinically. BTK inhibitors are the recommended second-line option for relapsed refractory cases. In this study, we describe institutional experience with the oral BTK inhibitor Zanubrutinib in combination with rituximab+/- HD-MTX (ZR/ZRM) in patients with central nervous system lymphoma. Aims: To evaluate efficacy and safety of Zanubrutinib, rituximab +/- HD-MTX in patients with primary CNS diffuse large B cell lymphoma. Methods: Zanubrutinib based ZR and ZRM regimen, Zanubrutinib 160mg twice a day, rituximab 375mg/m2 on day 0, MTX 3.5g/ m2 on day 1. After ZR or ZRM induction therapy, CR/CRu/PR patients partially received ASCT or radiotherapy consolidation therapy. Zanubrutinib is used as maintenance therapy, as desired, until the disease progresses. Results: A total of 26 patients with PCNSL were collected from July 1, 2020 to Feb 1, 2023. The median age was 60 years (range 38–76) and eleven were female（42.3%）. The median follow-up time was 19 months (range 3-32), 76.9% patients were treated with Zanubrutinib-containing regimen in the first-line treatment. 12month PFS rate is 45%；12month OS rate is 85%. The ORR in the 26 PCNSL patients was 76.9%, with 8 (30.8%) complete responses (CR) and 12 (46%) partial responses (PR), 4 (15.4%) stable disease (SD) and 2 (7.7%) progressive disease (PD) were observed. 20 patients received first-line treatment with ZR/ZRM, and ORR was 90% (8 CR,10 PR, 2 SD). 6 patients with ZR/ZRM as the second-line or above treatment had an ORR of 33.3% (2 PR, 2 SD, 2PD). Double-expressor lymphoma (DEL) has a shorter PFS than non-double-expressor PCNSL in our research center. The hematological toxicities were quite mild in 16 patients who cannot tolerate HD-MTX and treated with ZR alone. Including thrombocytopenia （Grade 1-2, n=2）, anaemia（Grade 1,n=1）,WBC count decreased（Grade 1,n=1）. It is worth noting that in patients who cannot tolerate high-dose chemoradiotherapy, ZR regimen shows a promising prospect. Summary/Conclusion: This study showed that ZR or ZRM was an effective and safety treatment for PCNSL patients. It is worth noting that in patients who cannot tolerate high-dose chemoradiotherapy, ZR regimen shows a promising prospect.Keywords: Clinical data, CNS lymphoma
The ERF transcription factor LTF1 activates DIR1 to control stereoselective synthesis of antiviral lignans and stress defense in Isatis indigotica roots
Authors: Ruibing Chen, Jian Yu, Luyao Yu, Liang Xiao, Ying Xiao, Junfeng Chen, Shouhong Gao, Xianghui Chen, Qing Li, Henan Zhang, Wansheng Chen, Lei Zhang
Journal: Acta Pharmaceutica Sinica B (2023)

Lignans are a powerful weapon for plants to resist stresses and have diverse bioactive functions to protect human health. Elucidating the mechanisms of stereoselective biosynthesis and response to stresses of lignans is important for the guidance of plant improvement. Here, we identified the complete pathway to stereoselectively synthesize antiviral (–)-lariciresinol glucosides in Isatis indigotica roots, which consists of three-step sequential stereoselective enzymes DIR1/2, PLR, and UGT71B2. DIR1 was further identified as the key gene in response to stresses and was able to trigger stress defenses by mediating the elevation in lignan content. Mechanistically, the phytohormone-responsive ERF transcription factor LTF1 colocalized with DIR1 in the cell periphery of the vascular regions in mature roots and helped resist biotic and abiotic stresses by directly regulating the expression of DIR1. These systematic results suggest that DIR1 as the first common step of the lignan pathway cooperates with PLR and UGT71B2 to stereoselectively synthesize (–)-lariciresinol derived antiviral lignans in I. indigotica roots and is also a part of the LTF1-mediated regulatory network to resist stresses. In conclusion, the LTF1-DIR1 module is an ideal engineering target to improve plant Defenses while increasing the content of valuable lignans in plants.
PB2152: THE CLINICAL PICTURE OF CASTLEMAN DISEASE – A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Karan Kanhai, Lisa Grant, Sarah Littler, Christian Hoffmann
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Castleman disease (CD) encompasses a spectrum of rare disorders with characteristic histopathological features, including unicentric (UCD), idiopathic multicentric (iMCD), and cases that are associated with the human herpes virus 8 (HHV8+MCD). Diagnostic guidelines are available for both UCD and iMCD, but not for HHV8+MCD. As the treatment options for each type of CD vary, it is important to be able to distinguish their presentation and determine the correct diagnosis. Aims: The aim of this study was to collate and compare the clinical presentations of different CD subtypes reported in the literature. Methods: A systematic review was performed of all publications reporting ≥5 patients with CD between 1995 and 2021, following the PRISMA guidelines. For each subtype of CD within each study, we extracted data on demographics, clinical symptoms, and laboratory parameters as stated in the international consensus diagnostic criteria for iMCD. As many of the included studies were published prior to these criteria and precise data were not available, we extended the criteria beyond the defined ranges. We then estimated the mean percentage of patients meeting each diagnostic criterion for each CD subtype using meta-analyses conducted with random-effects logistic regression models to account for between-study heterogeneity. Results: A total of 52 studies with 2456 cases from 16 countries were analysed, including 771 UCD, 1174 iMCD, and 511 HHV8+MCD cases. Many symptoms and laboratory abnormalities occurred at similar rates in iMCD and HHV8+MCD. However, compared with patients with HHV8+MCD, patients with iMCD had significantly lower rates of constitutional symptoms (46.6% versus 98.6%) and splenomegaly (48.2% versus 89.2%). In contrast, renal dysfunction appeared to be more common in iMCD (35.2% versus 11.4%). Patients with UCD had lower rates of clinical symptoms and laboratory abnormalities, though these were present also in this subgroup and were particularly pronounced in pediatric UCD. Summary/Conclusion: This systematic review and meta-analysis revealed that some systemic symptoms may be present in UCD. We found many similarities among the clinical presentations and laboratory findings in patients with iMCD and HHV8+MCD, but also some important differences. These differences probably reflect the heterogeneity of the underlying pathomechanisms and/or the different comorbidity burdens of these CD subtypes.Keywords: Systematic review, IL-6, Lymphoproliferative disorder
Where to now with the evolutionarily significant unit?
Authors: A. Rus Hoelzel
Journal: Trends in Ecology & Evolution (2023)

The designation of units for conservation has been a necessary but challenging objective since conservation efforts began. Most species are divided, typically by environment, into populations with independent evolutionary trajectories. There are practical conservation objectives for defining these boundaries. Separate genetic clusters provide future evolutionary potential as environments change, and individuals in isolated populations may lose fitness when population size is reduced. The history of the effort to define units is briefly reviewed here, but I focus on finding a process that may facilitate uniform and effective application at a time when conservation urgency is great. I propose a refinement of the designated unit concept, distinguishing between conservation units (CUs) and evolutionarily sustaining conservation units (ESCUs).
Restrictive Spirometry or PRISm: Does it Matter?
Authors: Caspar Schiffers, Tobias Mraz, Marie-Kathrin Breyer, Sylvia Hartl, Robab Breyer-Kohansal, Emiel F. M. Wouters
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Restrictive Spirometry or PRISm: Does it Matter?." American Journal of Respiratory and Critical Care Medicine, 208(8), pp. 905–907
Evolutionary neuroanatomical expansion of Broca’s region serving a human-specific function
Authors: Angela D. Friederici
Journal: Trends in Neurosciences (2023)

The question concerning the evolution of language is directly linked to the debate on whether language and action are dependent or not and to what extent Broca's region serves as a common neural basis. The debate resulted in two opposing views, one arguing for and one against the dependence of language and action mainly based on neuroscientific data. This article presents an evolutionary neuroanatomical framework which may offer a solution to this dispute. It is proposed that in humans, Broca's region houses language and action independently in spatially separated subregions. This became possible due to an evolutionary expansion of Broca's region in the human brain, which was not paralleled by a similar expansion in the chimpanzee's brain, providing additional space needed for the neural representation of language in humans.
International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023
Authors: Thomas P. Burris, Ian Mitchelle S. de Vera, Isabelle Cote, Colin A. Flaveny, Udayanga S. Wanninayake, Arindam Chatterjee, John K. Walker, Nickolas Steinauer, Jinsong Zhang, Laurel A. Coons, Kenneth S. Korach, Derek W. Cain, Anthony N. Hollenberg, Paul Webb, Douglas Forrest, Anton M. Jetten, Dean P. Edwards, Sandra L. Grimm, Sean Hartig, Carol A. Lange, Jennifer K. Richer, Carol A. Sartorius, Marc Tetel, Cyrielle Billon, Bahaa Elgendy, Lamees Hegazy, Kristine Griffett, Nahuel Peinetti, Kerry L. Burnstein, Travis S. Hughes, Sadichha Sitaula, Keitch R. Stayrook, Alexander Culver, Meghan H. Murray, Brian N. Finck, John A. Cidlowski
Journal: Pharmacological Reviews (2023)

The nuclear receptor (NR) superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiological processes. In this review, we will summarize and discuss recent progress in NR biology and drug development derived from the integration of various approaches, including biophysical techniques, structural studies, and translational investigations. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling. <b>Significance Statement</b> Nuclear receptors are ligand regulated transcription factors that function as key regulators of a wide range of physiological functions. NRs also serve as receptors for myriad drugs and in this review we provide an update of recent research into the function of this family of drug targets.
PB1971: A PHASE 1 MULTICENTER OPEN-LABEL DOSE-ESCALATION AND DOSE-EXPANSION STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, EFFICACY OF HS-10382 (TERN-70) IN CHRONIC MYELOID LEUKEMIA PATIENTS
Authors: Weiming LI, Na Xu, Zhongyuan Xu, Yanli Zhang, Junmin LI, Huanling Zhu, LI Zheng, Xiaojing Yan, Xin Du, Yu Hu
Journal: HemaSphere (2023)

Topic: 8. Chronic myeloid leukemia - Clinical Background: There is a need for new treatment options for patients (pts) with chronic myeloid leukemia (CML) who are intolerant/resistant to currently available BCR-ABL1 ATP-binding site targeted tyrosine kinase inhibitors (TKIs). HS-10382 (TERN-701) is a potent, oral small molecule allosteric inhibitor of BCR-ABL. By binding to the myristoyl site of the BCR-ABL1 protein, HS-10382 (TERN-701) locks BCR-ABL1 into an inactive conformation. This results in a mutation-driven resistance profile different from that of ATP-binding site TKIs, providing potential for both monotherapy and combination therapy with ATP-binding-site TKIs. In preliminary nonclinical assays, HS-10382 (TERN-701) was highly potent against wild type BCR-ABL1 as well as most common mutations acquired by pts treated with second generation active site TKIs. Aims: This ongoing first-in-human phase 1 study is evaluating HS-10382 (TERN-701) in pts with CML. Methods: Eligible adult CML chronic phase (CP) or advanced phase (AP) pts who are resistant or intolerant to prior BCR-ABL-1 TKI therapy are enrolled in an open-label Phase 1 study to evaluate the safety, tolerability, PK and efficacy of once-daily HS-10382 (TERN-701). This study is being conducted in two parts: Part 1 dose escalation utilizing a rolling six design and Part 2 dose expansion. In the dose escalation stage, CML-CP/AP pts who are resistant or intolerant to prior BCR-ABL-1 therapy are being enrolled to determine the maximum tolerated dose (MTD) or maximum applicable dose. Doses selected from the escalation part will be evaluated in the expansion stage in CML-CP pts who are resistant or intolerant to prior BCR-ABL-1 TKI therapy and have no T315I mutation. All pts will be carefully followed for adverse events for the duration of study treatment and for 28 days after the last dose of study drug. Pts will be permitted to continue therapy with assessments for progression if the study drug is well-tolerated and the pt has no objective evidence of disease progression. Results:Summary/Conclusion: This study is ongoing (enrollment underway for Part 1, dose 3 as of February 2023) with 7 participating study sites in China. Clinical trial information: NCT05367700. Keywords: Phase I, Chronic myeloid leukemia, BCR-ABL
P1120: NOVEL TARGETED AGENTS IN COMBINATION WITH R-ICE (R-ICE-X) BASED ON GENOTYPING IN RELAPSED/REFRACTORY DLBCL.
Authors: Shen Yige, Yi-Wen Cao, Shu Cheng, Peng-Peng Xu, LI Wang, Wei-LI Zhao
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtypes of aggressive non-Hodgkin lymphoma, which is characterized by high heterogeneity, rapid progression and poor prognosis. Different genetic subtypes of DLBCL have distinct oncogenic pathway features, gene expression profiles and variable clinical outcomes. Although approximately 60% of the patients can be cured by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), 30%-40% of the patients are relapsed or refractory to RCHOP, and only about 40% patients get benefits from second-line regimens such as R-ICE. The outcomes of these relapsed/refractory (R/R) DLBCL remain to be improved. Aims: This prospective study aims to investigate whether adding novel agents to R-ICE (R-ICE-X) based on genetic subtypes could improve clinical efficacy in R/R DLBCL. Methods: In this study, eligible patients with R/R DLBCL aged 18 -75 years were enrolled. All patients were assigned and stratified by genetic subtype, received different targeted regimen combined with R-ICE. The efficacy was evaluated after 3 courses R-ICE-X (every 21 days). Patients with CR/PR were subsequently treated with autologous hematopoietic stem cell transplantation or 3 courses of R-ICE-X consolidation and lenalidomide maintenance up to 12 months. See detail as the figure. The primary end point was overall response rate (ORR), and the secondary end points were 2-year progression-free survival (PFS) rate, 2-year overall survival (OS) rate, and safety evaluation. Results: At the time of data cut off, a total of 51 patients were enrolled, with a median age of 61(20-75) years. In the patients with R-ICE-zanubrutinib group (n=25), the ORR was 80%, with 12 patients (12/20, 60.0%) achieved CR and 4 patients (4/20, 20.0%) achieved PR. The 1-year PFS rate and OS rate were 57.9% and 79.4%, respectively. In the patients with lenalidomide combined with R-ICE (n=19), 12 patients (12/16, 75.0%) achieved CR, 0 patients achieved PR, and the ORR was 75.0%. The 1-year PFS and OS rates were 80.9% and 100.0%, respectively. The number of other groups needs to be further updated. Summary/Conclusion: R-ICE-zanubrutinib and R-ICE-lenalidomide therapy was well tolerated in all patients and showed clinically efficacy in patients with relapsed/ refractory DLBCL. The study is ongoing and further results will be continuously released.Keywords: Targeted therapy, Diffuse large B cell lymphoma
The opposing effects of two gene defects in STX11 and SLP76 on the disease in a patient with an inborn error of immunity
Authors: Rana Mansour, Rana El-Hassan, Youmna El-Orfali, Adam Saidu, Habib Al-Kalamouni, Qian Chen, Mehdi Benamar, Ghassan Dbaibo, Rima Hanna-Wakim, Talal A. Chatila, Michel J. Massaad
Journal: Journal of Allergy and Clinical Immunology (2023)
Gut microbiology of UK care home residents: a cross-sectional analysis from a randomised controlled trial
Authors: David Gillespie, Mandy Wootton, Ruby Ray, Philip C. Calder, Tin Man Mandy Lau, Eleri Owen-Jones, Rachel Lowe, Leanne Davies, Jennifer Richards, Kerenza Hood, Vivian Castro-Herrera, Jane Davies, Nick A. Francis, F.D. Richard Hobbs, Mark Lown, Michael Moore, Victoria Shepherd, Christopher C. Butler
Journal: Clinical Microbiology and Infection (2023)

To describe the prevalence of potentially clinically relevant gut pathogens and associations with the carriage of resistant organisms in UK care home residents.
T2T-YAO: A Telomere-to-Telomere Assembled Diploid Reference Genome for Han Chinese
Authors: Yukun He, Yanan Chu, Shuming Guo, Jiang Hu, Ran Li, Yali Zheng, Xinqian Ma, Zhenglin Du, Lili Zhao, Wenyi Yu, Jianbo Xue, Wenjie Bian, Feifei Yang, Xi Chen, Pingan Zhang, Rihan Wu, Yifan Ma, Changjun Shao, Jing Chen, Jian Wang, Jiwei Li, Jing Wu, Xiaoyi Hu, Qiuyue Long, Mingzheng Jiang, Hongli Ye, Shixu Song, Guangyao Li, Yue Wei, Yu Xu, Yanliang Ma, Yanwen Chen, Keqiang Wang, Jing Bao, Wen Xi, Fang Wang, Wentao Ni, Moqin Zhang, Yan Yu, Shengnan Li, Yu Kang, Zhancheng Gao
Journal: Genomics Proteomics & Bioinformatics (2023)

Since its initial release in 2001, the human reference genome has undergone continuous improvement in quality, and the recently released telomere-to-telomere (T2T) version - T2T-CHM13 - reaches its highest level of continuity and accuracy after 20 years of effort by working on a simplified, nearly homozygous genome of a hydatidiform mole cell line. Here, to provide an authentic complete diploid human genome reference for the Han Chinese, the largest population in the world, we assembled the genome of a male Han Chinese individual, T2T-YAO, which includes T2T assemblies of all the 22 + X + M and 22 + Y chromosomes in both haploids. The quality of T2T-YAO is much better than those of all currently available diploid assemblies, and its haploid version, T2T-YAO-hp, generated by selecting the better assembly for each autosome, reaches the top quality of fewer than one error per 29.5 Mb, even higher than that of T2T-CHM13. Derived from an individual living in the aboriginal region of the Han population, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors. Each haplotype of T2T-YAO possesses ∼ 330-Mb exclusive sequences, ∼ 3100 unique genes, and tens of thousands of nucleotide and structural variations as compared with CHM13, highlighting the necessity of a population-stratified reference genome. The construction of T2T-YAO, an accurate and authentic representative of the Chinese population, would enable precise delineation of genomic variations and advance our understandings in the hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.
PB1944: INDIVIDUALS WITH CHRONIC LYMPHOCYTIC LEUKAEMIA SHOW IMPAIRED HUMORAL BUT NORMAL CELLULAR IMMUNE RESPONSES AFTER RECEIVING A COMPLETE VACCINATION SCHEDULE AGAINST SARS-COV-2
Authors: Clara Sánchez-Menéndez, Magdalena Corona, Alejandro Zurdo, Alicia Simón-Rueda, Elena Mateos, Mario Manzanares, Javier García-Pérez, Mayte Pérez-Olmeda, Sara Rodríguez-Mora, María Aránzazu Murciano-Antón, Valentín García-Gutiérrez, Mayte Coiras, Montserrat Torres
Journal: HemaSphere (2023)

Topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical Background: Oncohematological patients may have a lower immune response against SARS-CoV-2, both to natural acquisition and vaccines. Chronic lymphocytic leukaemia (CLL) is the main cause of leukaemia in the western world, characterized by the accumulation of round B lymphocytes. Aims: This study aimed to describe the cellular and humoral immune response induced by SARS-CoV-2 vaccination in CLL patients. Methods: Prospective, observational, longitudinal study with 14 individuals with CLL under the standard-of-care treatment and 11 in the “watch and wait” strategy who had mild COVID-19. Twelve healthy donors who recovered from mild COVID-19 were controls. Peripheral blood samples and clinical data were collected at baseline, one month after the second dose (Sample 1), and one and six months after the booster, respectively (Samples 2 and 3). Direct cellular cytotoxicity (DCC) of PBMCs on Vero E6 cells infected with pseudotyped SARS-CoV-2 was determined and cell populations were analyzed by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) was performed by using Annexin V and rituximab-coated Raji cells as targets. Results: 1) Median age of participants was 74 years (IQR 66.0-80.5) and 76 years (IQR: 66.0-80.5) under the standard-of-care treatment and “watch and wait”, respectively. In both groups, most individuals (71.4% and 63.6%, respectively) were men. 2) DCC was similar to healthy donors in individuals from both groups of study. 3) Similarly, no differences were found in ADCC when compared to healthy donors’ response. 3) During the follow-up, 57.1% of patients under treatment did not develop detectable levels of IgGs after vaccination versus 9.1% of the patients in the “watch and wait” strategy (p<0.0001). 4) Levels of IgGs were significantly reduced (11.2-, 3.6- and 11.3-fold; p<0.0001) in samples 2, 3 and 4 in individuals on treatment in comparison with healthy donors. Summary/Conclusion: Individuals with CLL showed low levels of IgGs against SARS-CoV-2 after a complete vaccination schedule against SARS-CoV-2, although the cellular immune response was comparable to healthy donors, which may prevent that these individuals may have severe breakthough infections with SARS-CoV-2. Keywords: Vaccination, Immune response, Chronic lymphocytic leukemia
Reply to Xiao Li, Zicheng Xu, and Feng Qi’s Letter to the Editor re: Soumyajit Roy, Yilun Sun, Scott C. Morgan, et al. Effect of Prior Local Therapy on Response to First-line Androgen Receptor Axis Targeted Therapy in Metastatic Castrate-resistant Prostate Cancer: A Secondary Analysis of the COU-AA-302 Trial. Eur Urol 2023;83:571–9
Authors: Soumyajit Roy, Yilun Sun, Scott Morgan, Shawn Malone
Journal: European Urology (2023)
Phase 2 Trial of Atezolizumab in Bacillus Calmette-Guérin–unresponsive High-risk Non–muscle-invasive Bladder Cancer: SWOG S1605
Authors: Peter C. Black, Catherine M. Tangen, Parminder Singh, David J. McConkey, M. Scott Lucia, William T. Lowrance, Vadim S. Koshkin, Kelly L. Stratton, Trinity J. Bivalacqua, Wassim Kassouf, Sima P. Porten, Rick Bangs, Melissa Plets, Ian M. Thompson, Seth P. Lerner
Journal: European Urology (2023)